Nearly 100 million people in the world, including approximately 57 million in Bangladesh and about 15 million in the U.S., are chronically exposed to inorganic arsenic, a Class I human carcinogen, and are at increased risk of skin and[unreadable] other arsenic-induced cancers?as well as cardiovascular, pulmonary and other non-malignant disorders.[unreadable] As part of the Columbia University Superfund Basic Research Program, we have established Health Effects[unreadable] of Arsenic Longitudinal Study (HEALS)?a large prospective cohort study based on individual level data[unreadable] among a population exposed to a wide range of inorganic arsenic (InAs) from drinking water in Araihazar,[unreadable] Bangladesh. Over the past five years, using a population-based sampling frame, we recruited 11,754 men[unreadable] and women (with >99% response rates) and collected detailed questionnaires, clinical data, and[unreadable] biospecimen samples from them at baseline, two years and four years after recruitment. Through a[unreadable] dedicated medical clinic established by Columbia University to exclusively serve the HEALS participants, we[unreadable] have also developed an effective mechanism of following the cohort, especially for detecting incidence and[unreadable] mortality of dermatological, pulmonary, and cardiovascular disorders (CVD). In this proposal, we proposed[unreadable] to prospectively evaluate the effects of various measures of As exposure and metabolism on: i) incidence of[unreadable] skin lesions and skin cancer, ii) incidence and mortality from chronic lung disorders and mortality from lung[unreadable] cancers, iii) incidence and mortality from CVD, iv) serum levels of the epidermal growth factor receptor (as[unreadable] an early biomarker of As-induced skin carcinogenesis), v) serum levels of bronchial/alveolar cell-derived[unreadable] antioxidant Clara cell protein 16 (as an early biomarker of As-induced chronic lung damage and[unreadable] carcinogenesis), and vi) carotid artery intima-medial thickness (as early preclinical marker of As-induced[unreadable] vascular damage). A combination of prospective cohort, case-cohort, cross-sectional and case-control study[unreadable] designs will be employed to address these Specific Aims in the most efficient manner. In addition to[unreadable] investigating these novel research questions, as in the previous funding period, the HEALS will continue to[unreadable] support other biomedical research projects (including Projects 1 and 4 of the proposed program). This will[unreadable] be the first prospective cohort study using individual level data on As exposure and metabolism, and findings[unreadable] from this study will be directly relevant for both research and policy issues pertaining to the health of millions[unreadable] of people around the world.